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1.
J Dermatol ; 46(7): 622-625, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31106887

RESUMO

Severe dermatitis, multiple allergies and metabolic wasting (SAM) syndrome is a recently recognized syndrome caused by mutations in the desmoglein 1 (DSG1) and desmoplakin (DSP) genes. Only two cases of SAM-DSP have been reported. We report on a 2-year-old girl presenting with pustular lakes within areas of erythema and large accumulations of intraepidermal neutrophils, which initially led to our misdiagnosis of generalized pustular psoriasis. No mutation was found in either the IL36RN or CARD14 genes by Sanger sequencing. The distinctive manifestations of erythroderma with severe itching, hypotrichosis, enamel defects, onychodystrophy, palmoplantar keratoderma and the crucial result of de novo missense mutation in exon 14 of the DSP gene (c.1828T>C, p.S610P) discovered by next-generation sequencing finally confirmed the diagnosis of SAM syndrome. The eruptions significantly improved after a 4-week treatment with oral acitretin and topical pimecrolimus. Oral gabapentin was prescribed simultaneously for 4 months, relieving her skin pruritus and suggesting that early treatment with pimecrolimus, acitretin and gabapentin for SAM-DSP syndrome is effective. It may even inhibit multiple allergies induced by skin barrier injury. In this work we also review the clinical features, differential diagnoses and pathological manifestations of SAM-DSP syndrome.


Assuntos
Acitretina/administração & dosagem , Dermatite Esfoliativa/diagnóstico , Desmoplaquinas/genética , Gabapentina/administração & dosagem , Hipersensibilidade/diagnóstico , Síndrome de Emaciação/diagnóstico , Administração Cutânea , Administração Oral , Pré-Escolar , Análise Mutacional de DNA , Dermatite Esfoliativa/tratamento farmacológico , Dermatite Esfoliativa/genética , Dermatite Esfoliativa/patologia , Diagnóstico Diferencial , Erros de Diagnóstico , Feminino , Humanos , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/genética , Hipersensibilidade/patologia , Mutação de Sentido Incorreto , Psoríase/diagnóstico , Índice de Gravidade de Doença , Pele/efeitos dos fármacos , Pele/patologia , Síndrome , Tacrolimo/administração & dosagem , Tacrolimo/análogos & derivados , Resultado do Tratamento , Síndrome de Emaciação/tratamento farmacológico , Síndrome de Emaciação/genética , Síndrome de Emaciação/patologia
2.
Toxicol Sci ; 165(2): 347-360, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29873790

RESUMO

The aryl hydrocarbon receptor (AHR) mediates the toxic effects of dioxin (2, 3, 7, 8-tetrachlorodibenzo-p-dioxin; TCDD), which includes thymic atrophy, steatohepatitis, and a lethal wasting syndrome in laboratory rodents. Although the mechanisms of dioxin toxicity remain unknown, AHR signaling in hepatocytes is necessary for dioxin-induced liver toxicity. We previously reported that loss of TCDD-inducible poly(adenosine diphosphate [ADP]-ribose) polymerase (TIPARP/PARP7/ARTD14), an AHR target gene and mono-ADP-ribosyltransferase, increases the sensitivity of mice to dioxin-induced toxicities. To test the hypothesis that TIPARP is a negative regulator of AHR signaling in hepatocytes, we generated Tiparpfl/fl mice in which exon 3 of Tiparp is flanked by loxP sites, followed by Cre-lox technology to create hepatocyte-specific (Tiparpfl/flCreAlb) and whole-body (Tiparpfl/flCreCMV; TiparpEx3-/-) Tiparp null mice. Tiparpfl/flCreAlb and TiparpEx3-/- mice given a single injection of 10 µg/kg dioxin did not survive beyond days 7 and 9, respectively, while all Tiparp+/+ mice survived the 30-day treatment. Dioxin-exposed Tiparpfl/flCreAlb and TiparpEx3-/- mice had increased steatohepatitis and hepatotoxicity as indicated by greater staining of neutral lipids and serum alanine aminotransferase activity than similarly treated wild-type mice. Tiparpfl/flCreAlb and TiparpEx3-/- mice exhibited augmented AHR signaling, denoted by increased dioxin-induced gene expression. Metabolomic studies revealed alterations in lipid and amino acid metabolism in liver extracts from Tiparpfl/flCreAlb mice compared with wild-type mice. Taken together, these data illustrate that TIPARP is an important negative regulator of AHR activity, and that its specific loss in hepatocytes is sufficient to increase sensitivity to dioxin-induced steatohepatitis and lethality.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fígado Gorduroso/induzido quimicamente , Hepatócitos/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/genética , Dibenzodioxinas Policloradas/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Síndrome de Emaciação/induzido quimicamente , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Fígado Gorduroso/enzimologia , Fígado Gorduroso/genética , Expressão Gênica/efeitos dos fármacos , Hepatócitos/enzimologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Camundongos , Camundongos Knockout , Cultura Primária de Células , Deleção de Sequência , Transdução de Sinais , Síndrome de Emaciação/enzimologia , Síndrome de Emaciação/genética
3.
Proc Natl Acad Sci U S A ; 115(27): 7069-7074, 2018 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-29915091

RESUMO

Standing genetic variation enables or restricts a population's capacity to respond to changing conditions, including the extreme disturbances expected to increase in frequency and intensity with continuing anthropogenic climate change. However, we know little about how populations might respond to extreme events with rapid genetic shifts, or how population dynamics may influence and be influenced by population genomic change. We use a range-wide epizootic, sea star wasting disease, that onset in mid-2013 and caused mass mortality in Pisaster ochraceus to explore how a keystone marine species responded to an extreme perturbation. We integrated field surveys with restriction site-associated DNA sequencing data to (i) describe the population dynamics of mortality and recovery, and (ii) compare allele frequencies in mature P. ochraceus before the disease outbreak with allele frequencies in adults and new juveniles after the outbreak, to identify whether selection may have occurred. We found P. ochraceus suffered 81% mortality in the study region between 2012 and 2015, and experienced a concurrent 74-fold increase in recruitment beginning in late 2013. Comparison of pre- and postoutbreak adults revealed significant allele frequency changes at three loci, which showed consistent changes across the large majority of locations. Allele frequency shifts in juvenile P. ochraceus (spawned from premortality adults) were consistent with those seen in adult survivors. Such parallel shifts suggest detectable signals of selection and highlight the potential for persistence of this change in subsequent generations, which may influence the resilience of this keystone species to future outbreaks.


Assuntos
Alelos , Frequência do Gene , Estrelas-do-Mar/genética , Síndrome de Emaciação/genética , Síndrome de Emaciação/veterinária , Animais
4.
Exp Dermatol ; 27(7): 787-790, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29604126

RESUMO

Severe skin dermatitis, multiple allergies and metabolic wasting (SAM) syndrome is a rare life-threatening inherited condition caused by bi-allelic mutations in DSG1 encoding desmoglein 1. The disease was initially reported to manifest with severe erythroderma, failure to thrive, atopic manifestations, recurrent infections, hypotrichosis and palmoplantar keratoderma. We present 3 new cases of SAM syndrome in 2 families and review the cases published so far. Whole exome and direct sequencing were used to identify SAM syndrome-causing mutations. Consistent with previous data, SAM syndrome was found in all 3 patients to result from homozygous mutations in DSG1 predicted to result in premature termination of translation. In contrast, as compared with patients previously reported, the present cases were found to display a wide range of clinical presentations of variable degrees of severity. The present data emphasize the fact that SAM syndrome is characterized by extensive phenotypic heterogeneity, suggesting the existence of potent modifier traits.


Assuntos
Dermatite/genética , Desmogleína 1/genética , Hipersensibilidade/genética , Síndrome de Emaciação/genética , Adolescente , Substituição de Aminoácidos , Pré-Escolar , Códon sem Sentido , Análise Mutacional de DNA , Dermatite/patologia , Feminino , Heterozigoto , Homozigoto , Humanos , Ceratodermia Palmar e Plantar/genética , Ceratodermia Palmar e Plantar/patologia , Mutação com Perda de Função , Masculino , Linhagem , Fenótipo , Mutação Puntual , Síndrome
6.
Hum Gene Ther ; 29(3): 390-399, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28967304

RESUMO

Striated muscle wasting occurs with a variety of disease indications, contributing to mortality and compromising life quality. Recent studies indicate that the recombinant adeno-associated virus (serotype 6) Smad7 gene therapeutic, AVGN7, enhances skeletal and cardiac muscle mass and prevents cancer-induced wasting of both tissues. This is accomplished by attenuating ActRIIb intracellular signaling and, as a result, the physiological actions of myostatin and other ActRIIb ligands. AVGN7 also enhances isolated skeletal muscle twitch force, but is unknown to improve systemic muscle function similarly, especially exercise capacity. A 2-month-long dose-escalation study was therefore conducted using 5 × 1011, 1 × 1012, and 5 × 1012 vg/mouse and different tests of systemic muscle function. Body mass, skeletal muscle mass, heart mass, and forelimb grip strength were all increased in a dose-dependent manner, as was the fiber cross-sectional area of tibialis anterior muscles. Maximal oxygen consumption (VO2max), a measure of metabolic rate, was similarly enhanced during forced treadmill running, and although the total distance traveled was only elevated by the highest dose, all doses reduced the energy expenditure rate compared to control mice injected with an empty vector. Such improvements in VO2max are consistent with physiological cardiac hypertrophy, which is highly beneficial and a normal adaptive response to exercise. This was particularly evident at the lowest dose tested, which had minimal significant effects on skeletal muscle mass and/or function, but increased heart weight and exercise capacity. These results together suggest that AVGN7 enhances striated muscle mass and systemic muscle function. They also define minimally effective and optimal doses for future preclinical trials and toxicology studies and in turn will aid in establishing dose ranges for clinical trials.


Assuntos
Dependovirus , Terapia Genética , Força Muscular , Músculo Esquelético , Condicionamento Físico Animal , Proteína Smad7 , Animais , Camundongos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Doenças Musculares/genética , Doenças Musculares/fisiopatologia , Doenças Musculares/terapia , Consumo de Oxigênio , Proteína Smad7/biossíntese , Proteína Smad7/genética , Síndrome de Emaciação/genética , Síndrome de Emaciação/fisiopatologia , Síndrome de Emaciação/terapia
7.
Sci Rep ; 7(1): 2273, 2017 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-28536426

RESUMO

Cancer-induced cachexia, characterized by muscle wasting, is a lethal metabolic syndrome with undefined etiology. Current consensus is that multiple factors contribute to cancer-induced muscle wasting, and therefore therapy requires combinational strategies. Here, we show that Toll-like receptor 4 (TLR4) mediates cancer-induced muscle wasting by directly activating muscle catabolism as well as stimulating an innate immune response in mice bearing Lewis lung carcinoma (LLC), and targeting TLR4 alone effectively abrogate muscle wasting. Utilizing specific siRNAs we observed that LLC cell-conditioned medium (LCM)-treated C2C12 myotubes underwent a rapid catabolic response in a TLR4-dependent manner, including activation of the p38 MAPK-C/EBPß signaling pathway as well as the ubiquitin-proteasome and autophagy-lysosome pathways, resulting in myotube atrophy. Utilizing a reporter cell-line it was confirmed that LCM activated TLR4. These results suggest that LLC-released cachexins directly activate muscle catabolism via activating TLR4 on muscle cells independent of immune responses. Critically, LLC tumor-bearing TLR4-/- mice were spared from muscle wasting due to a blockade in muscle catabolic pathways. Further, tumor-induced elevation of circulating TNFα and interleukin-6 (IL-6) was abolished in TLR4-/- mice. These data suggest that TLR4 is a central mediator and therapeutic target of cancer-induced muscle wasting.


Assuntos
Carcinoma Pulmonar de Lewis/metabolismo , Músculo Esquelético/metabolismo , Receptor 4 Toll-Like/metabolismo , Síndrome de Emaciação/metabolismo , Animais , Carcinoma Pulmonar de Lewis/complicações , Carcinoma Pulmonar de Lewis/genética , Linhagem Celular , Linhagem Celular Tumoral , Meios de Cultivo Condicionados/farmacologia , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/patologia , Proteólise , Interferência de RNA , Transdução de Sinais , Receptor 4 Toll-Like/genética , Síndrome de Emaciação/etiologia , Síndrome de Emaciação/genética
10.
Mol Med Rep ; 14(4): 3676-82, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27601064

RESUMO

The temporomandibular joint (TMJ), a unique synovial joint whose development differs from that of other synovial joints, develops from two distinct mesenchymal condensations that grow toward each other and ossify through different mechanisms. The short stature homeobox 2 (Shox2) gene serves an important role in TMJ development and previous studies have demonstrated that Shox2SHOX KI/KI mice display a TMJ defective phenotype, congenital dysplasia and premature eroding of the articular disc, which is clinically defined as a TMJ disorder. In the present study, Shox2SHOX KI/KI mouse models were used to investigate the mechanisms of congenital osteoarthritis (OA)­like disease during postnatal TMJ growth. Shox2SHOX KI/KI mice were observed to develop a severe muscle wasting syndrome from day 7 postnatal. Histological examination indicated that the condyle and glenoid fossa of Shox2SHOX KI/KI mice was reduced in size in the second week after birth. The condyles of Shox2SHOX KI/KI mice exhibited reduced expression levels of collagen type II and Indian hedgehog, and increased expression of collagen type I. A marked increase in matrix metalloproteinase 9 (MMP9) and MMP13 in the condyles was also observed. These cellular and molecular defects may contribute to the observed (OA)­like phenotype of Shox2SHOX KI/KI mouse TMJs.


Assuntos
Proteínas de Homeodomínio/genética , Osteoartrite/genética , Transtornos da Articulação Temporomandibular/genética , Articulação Temporomandibular/patologia , Animais , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Colágeno Tipo I/análise , Colágeno Tipo II/análise , Modelos Animais de Doenças , Feminino , Expressão Gênica , Técnicas de Introdução de Genes , Humanos , Masculino , Metaloproteinase 13 da Matriz/análise , Metaloproteinase 9 da Matriz/análise , Camundongos , Camundongos Endogâmicos C57BL , Osteoartrite/patologia , Proteína de Homoeobox de Baixa Estatura , Articulação Temporomandibular/metabolismo , Transtornos da Articulação Temporomandibular/patologia , Síndrome de Emaciação/genética , Síndrome de Emaciação/patologia
11.
Proc Natl Acad Sci U S A ; 113(31): E4494-503, 2016 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-27418600

RESUMO

Innervation of skeletal muscle by motor neurons occurs through the neuromuscular junction, a cholinergic synapse essential for normal muscle growth and function. Defects in nerve-muscle signaling cause a variety of neuromuscular disorders with features of ataxia, paralysis, skeletal muscle wasting, and degeneration. Here we show that the nuclear zinc finger protein ZFP106 is highly enriched in skeletal muscle and is required for postnatal maintenance of myofiber innervation by motor neurons. Genetic disruption of Zfp106 in mice results in progressive ataxia and hindlimb paralysis associated with motor neuron degeneration, severe muscle wasting, and premature death by 6 mo of age. We show that ZFP106 is an RNA-binding protein that associates with the core splicing factor RNA binding motif protein 39 (RBM39) and localizes to nuclear speckles adjacent to spliceosomes. Upon inhibition of pre-mRNA synthesis, ZFP106 translocates with other splicing factors to the nucleolus. Muscle and spinal cord of Zfp106 knockout mice displayed a gene expression signature of neuromuscular degeneration. Strikingly, altered splicing of the Nogo (Rtn4) gene locus in skeletal muscle of Zfp106 knockout mice resulted in ectopic expression of NOGO-A, the neurite outgrowth factor that inhibits nerve regeneration and destabilizes neuromuscular junctions. These findings reveal a central role for Zfp106 in the maintenance of nerve-muscle signaling, and highlight the involvement of aberrant RNA processing in neuromuscular disease pathogenesis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Músculo Esquelético/metabolismo , Atrofia Muscular/genética , Síndrome de Emaciação/genética , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Animais , Células COS , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Denervação Muscular , Músculo Esquelético/inervação , Músculo Esquelético/patologia , Atrofia Muscular/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Síndrome de Emaciação/metabolismo
12.
J Dermatol ; 43(10): 1201-1204, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27154412

RESUMO

Recently, homozygous mutations in the desmoglein-1 (DSG1) gene and heterozygous mutation in the desmoplakin (DSP) gene have been demonstrated to be associated with severe dermatitis, multiple allergies and metabolic wasting (SAM) syndrome (Mendelian Inheritance in Man no. 615508). We aim to identify the molecular basis for a Chinese pedigree of SAM syndrome. A Chinese pedigree of SAM syndrome was subjected to mutation detection in the DSG1 gene. Sequence analysis of the DSG1 gene and quantitative reverse transcriptase polymerase chain reaction analysis for gene expression of DSG1 using cDNA derived from the epidermis of patients and controls were both performed. Skin biopsies were also taken from patients for pathological study and transmission electron microscopy observation. Novel homozygous splicing mutation c.1892-1delG in the exon-intron border of the DSG1 gene has been demonstrated to be associated with SAM syndrome. We report a new family of SAM syndrome of Asian decent and expand the spectrum of mutations in the DSG1 gene.


Assuntos
Dermatite/genética , Desmogleína 1/genética , Hipersensibilidade/genética , Ceratodermia Palmar e Plantar/genética , Síndrome de Emaciação/genética , Adolescente , Biópsia , Criança , DNA Complementar/genética , Epiderme/metabolismo , Feminino , Homozigoto , Humanos , Masculino , Mutação , Linhagem , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Pele/patologia , Síndrome
13.
J Clin Invest ; 126(2): 667-80, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26784541

RESUMO

CYP24A1 (hereafter referred to as CYP24) enzymatic activity is pivotal in the inactivation of vitamin D metabolites. Basal renal and extrarenal CYP24 is usually low but is highly induced by its substrate 1,25-dihydroxyvitamin D. Unbalanced high and/or long-lasting CYP24 expression has been proposed to underlie diseases like chronic kidney disease, cancers, and psoriasis that otherwise should favorably respond to supplemental vitamin D. Using genetically modified mice, we have shown that renal phosphate wasting hypophosphatemic states arising from high levels of fibroblast growth factor 23 (FGF23) are also associated with increased renal Cyp24 expression, suggesting that elevated CYP24 activity is pivotal to the pathophysiology of these disorders. We therefore crossed 2 mouse strains, each with distinct etiology for high levels of circulating FGF23, onto a Cyp24-null background. Specifically, we evaluated Cyp24 deficiency in Hyp mice, the murine homolog of X-linked dominant hypophosphatemic rickets, and transgenic mice that overexpress a mutant FGF23 (FGF23R176Q) that is associated with the autosomal dominant form of hypophosphatemic rickets. Loss of Cyp24 in these murine models of human disease resulted in near-complete recovery of rachitic/osteomalacic bony abnormalities in the absence of any improvement in the serum biochemical profile. Moreover, treatment of Hyp and FGF23R1760-transgenic mice with the CYP24 inhibitor CTA102 also ameliorated their rachitic bones. Our results link CYP24 activity to the pathophysiology of FGF23-dependent renal phosphate wasting states and implicate pharmacologic CYP24 inhibition as a therapeutic adjunct for their treatment.


Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacologia , Fatores de Crescimento de Fibroblastos/metabolismo , Fosfatos/urina , Insuficiência Renal Crônica , Vitamina D3 24-Hidroxilase/antagonistas & inibidores , Síndrome de Emaciação , Animais , Modelos Animais de Doenças , Feminino , Fatores de Crescimento de Fibroblastos/genética , Humanos , Camundongos , Camundongos Knockout , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/urina , Vitamina D3 24-Hidroxilase/genética , Vitamina D3 24-Hidroxilase/metabolismo , Síndrome de Emaciação/tratamento farmacológico , Síndrome de Emaciação/genética , Síndrome de Emaciação/patologia , Síndrome de Emaciação/urina
15.
J Allergy Clin Immunol ; 136(5): 1268-76, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26073755

RESUMO

BACKGROUND: Severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome is a recently recognized syndrome caused by mutations in the desmoglein 1 gene (DSG1). To date, only 3 families have been reported. OBJECTIVE: We studied a new case of SAM syndrome known to have no mutations in DSG1 to detail the clinical, histopathologic, immunofluorescent, and ultrastructural phenotype and to identify the underlying molecular mechanisms in this rare genodermatosis. METHODS: Histopathologic, electron microscopy, and immunofluorescent studies were performed. Whole-exome sequencing data were interrogated for mutations in desmosomal and other skin structural genes, followed by Sanger sequencing of candidate genes in the patient and his parents. RESULTS: No mutations were identified in DSG1; however, a novel de novo heterozygous missense c.1757A>C mutation in the desmoplakin gene (DSP) was identified in the patient, predicting the amino acid substitution p.His586Pro in the desmoplakin polypeptide. CONCLUSIONS: SAM syndrome can be caused by mutations in both DSG1 and DSP. Knowledge of this genetic heterogeneity is important for both analysis of patients and genetic counseling of families. This condition and these observations reinforce the importance of heritable skin barrier defects, in this case desmosomal proteins, in the pathogenesis of atopic disease.


Assuntos
Dermatite/genética , Desmoplaquinas/genética , Hipersensibilidade/genética , Mutação de Sentido Incorreto/genética , Síndrome de Emaciação/genética , Criança , Pré-Escolar , Análise Mutacional de DNA , Dermatite/diagnóstico , Desmogleína 1/genética , Progressão da Doença , Humanos , Hipersensibilidade/diagnóstico , Lactente , Recém-Nascido , Masculino , Linhagem , Estrutura Terciária de Proteína/genética , Pele/patologia , Síndrome de Emaciação/diagnóstico
16.
PLoS One ; 10(5): e0128150, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26020776

RESUMO

Sea star wasting disease (SSWD) describes a suite of symptoms reported in asteroids of the North American Pacific Coast. We performed a metatranscriptomic survey of asymptomatic and symptomatic sunflower star (Pycnopodia helianthoides) body wall tissues to understand holobiont gene expression in tissues affected by SSWD. Metatranscriptomes were highly variable between replicate libraries, and most differentially expressed genes represented either transcripts of associated microorganisms (particularly Pseudomonas and Vibrio relatives) or low-level echinoderm transcripts of unknown function. However, the pattern of annotated host functional genes reflects enhanced apoptotic and tissue degradation processes and decreased energy metabolism, while signalling of death-related proteins was greater in asymptomatic and symptomatic tissues. Our results suggest that the body wall tissues of SSWD-affected asteroids may undergo structural changes during disease progression, and that they are stimulated to undergo autocatalytic cell death processes.


Assuntos
Metabolismo Energético , Regulação da Expressão Gênica , Estrelas-do-Mar/metabolismo , Transcriptoma , Síndrome de Emaciação/metabolismo , Síndrome de Emaciação/veterinária , Animais , Estrelas-do-Mar/genética , Síndrome de Emaciação/genética , Síndrome de Emaciação/patologia
17.
Cell Biol Int ; 39(6): 666-77, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25644094

RESUMO

We previously identified the insertion of an intracisternal A-particle retrotransposons (IAPs) sequence in a gene, 9630033F20Rik, that contains domains involved in glycolysis from a mouse model called lethal wasting (lew). However, because both IAP insertion and the muation of vesicle-associated membrane protein 1 (VAMP1) were discovered from lew, the impact of the IAP insertion and Vamp1 on the lew mouse phenotype needs further investigation. In this study, the effect of the 9630033F20Rik and Vamp1 on glycolysis and muscle-wasting genes in heart, muscle, and brain tissues was further investigated using data of gene expression profiles in these tissues. Our data indicated that the expression levels of 9630033F20Rik and Vamp1 are not associated with each other. While 9630033F20Rik affects the expression of several key genes in pathways of glycolysis and muscle wasting, Vamp1 affects a different set of genes, with fewer numbers. In situ hybridization indicated that the expression of 9630033F20Rik is different in musculoskeletal tissues between the muscle-wasting mouse model and the wild-type model. Our data indicated that 9630033F20Rik may play an important role in muscle wasting and that it has a distinguished characterization of gene network. Our data also suggest that both 9630033F20Rik and Vamp1 play functional roles in muscle development and lead to the muscle-wasting phenotype when they are mutated.


Assuntos
Redes Reguladoras de Genes , Músculos/enzimologia , Músculos/patologia , Fosfoglicerato Mutase/genética , Síndrome de Emaciação/enzimologia , Síndrome de Emaciação/genética , Animais , Regulação da Expressão Gênica , Glicólise/genética , Hibridização In Situ , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Fosfoglicerato Mutase/metabolismo , Reprodutibilidade dos Testes , Proteína 1 Associada à Membrana da Vesícula/genética , Proteína 1 Associada à Membrana da Vesícula/metabolismo
18.
Toxicology ; 328: 93-101, 2015 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-25529477

RESUMO

In some mammals, halogenated aromatic hydrocarbon (HAH) exposure causes wasting syndrome, defined as significant weight loss associated with lethal outcomes. The most potent HAH in causing wasting is 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD), which exerts its toxic effects through the aryl hydrocarbon receptor (AHR). Since TCDD toxicity is thought to predominantly arise from dysregulation of AHR-transcribed genes, it was hypothesized that wasting syndrome is a result of to TCDD-induced dysregulation of genes involved in regulation of food-intake. As the hypothalamus is the central nervous systems' regulatory center for food-intake and energy balance. Therefore, mRNA abundances in hypothalamic tissue from two rat strains with widely differing sensitivities to TCDD-induced wasting syndrome: TCDD-sensitive Long-Evans rats and TCDD-resistant Han/Wistar rats, 23h after exposure to TCDD (100µg/kg) or corn oil vehicle. TCDD exposure caused minimal transcriptional dysregulation in the hypothalamus, with only 6 genes significantly altered in Long-Evans rats and 15 genes in Han/Wistar rats. Two of the most dysregulated genes were Cyp1a1 and Nqo1, which are induced by TCDD across a wide range of tissues and are considered sensitive markers of TCDD exposure. The minimal response of the hypothalamic transcriptome to a lethal dose of TCDD at an early time-point suggests that the hypothalamus is not the predominant site of initial events leading to hypophagia and associated wasting. TCDD may affect feeding behaviour via events upstream or downstream of the hypothalamus, and further work is required to evaluate this at the level of individual hypothalamic nuclei and subregions.


Assuntos
Perfilação da Expressão Gênica/métodos , Hipotálamo/efeitos dos fármacos , Análise de Sequência com Séries de Oligonucleotídeos , Dibenzodioxinas Policloradas/toxicidade , Toxicogenética/métodos , Transcrição Genética/efeitos dos fármacos , Síndrome de Emaciação/induzido quimicamente , Síndrome de Emaciação/genética , Animais , Citocromo P-450 CYP1A1/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , NAD(P)H Desidrogenase (Quinona)/genética , RNA Mensageiro/metabolismo , Ratos Long-Evans , Ratos Wistar , Especificidade da Espécie , Fatores de Tempo
19.
Br J Dermatol ; 172(1): 257-61, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25041099

RESUMO

Monoallelic desmoglein 1 mutations have been known for many years to cause striate palmoplantar keratoderma, but only recently, biallelic loss-of-function mutations were associated with a new disorder, designated as SAM syndrome (comprising severe dermatitis, multiple allergies and metabolic wasting) in two consanguineous families. We report on a new case from a third independent family with the homozygous nonsense mutation, c.2659C>T, p.R887* in exon 15 of DSG1 (desmoglein 1 gene). This mutation led to mRNA decay and loss of expression of desmoglein 1. The clinical phenotype consisted of severe palmoplantar keratoderma, dermatitis and multiple allergies. In contrast to the previous cases, malabsorption, hypoalbuminaemia, developmental delay, hypotrichosis or severe recurrent infections were not observed.


Assuntos
Códon sem Sentido/genética , Dermatite/genética , Desmogleína 1/genética , Hipersensibilidade/genética , Ceratodermia Palmar e Plantar/genética , Adolescente , Feminino , Homozigoto , Humanos , Síndrome de Emaciação/genética
20.
PLoS One ; 9(1): e87587, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24498144

RESUMO

BACKGROUND: Skeletal muscle wasting in acute lung injury (ALI) patients increases the morbidity and mortality associated with this critical illness. The contribution of laryngeal muscle wasting to these outcomes is unknown, though voice impairments and aspiration are common in intensive care unit (ICU) survivors. We evaluated the intrinsic laryngeal abductor (PCA, posterior cricoarytenoid), adductor (CT, cricothyroid) and limb (EDL, extensor digitorum longus) muscles in a mouse model of ALI. METHODS: Escherichia coli lipopolysaccharides were instilled into the lungs of adult male C57Bl6J mice (ALI mice). Limb and intrinsic laryngeal muscles were analyzed for fiber size, type, protein expression and myosin heavy chain (MyHC) composition by SDS-PAGE and mass spectroscopy. RESULTS: Marked muscle atrophy occurred in the CT and EDL muscles, while the PCA was spared. The E3 ubiquitin ligase muscle ring finger-1 protein (MuRF1), a known mediator of limb muscle atrophy in this model, was upregulated in the CT and EDL, but not in the PCA. Genetic inhibition of MuRF1 protected the CT and EDL from ALI-induced muscle atrophy. MyHC-Extraocular (MyHC-EO) comprised 27% of the total MyHC in the PCA, distributed as hybrid fibers throughout 72% of PCA muscle fibers. CONCLUSION: The vocal cord abductor (PCA) contains a large proportion of fibers expressing MyHC-EO and is spared from muscle atrophy in ALI mice. The lack of MuRF1 expression in the PCA suggests a previously unrecognized mechanism whereby this muscle is spared from atrophy. Atrophy of the vocal cord adductor (CT) may contribute to the impaired voice and increased aspiration observed in ICU survivors. Further evaluation of the sparing of muscles involved in systemic wasting diseases may lead to potential therapeutic targets for these illnesses.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Músculos Laríngeos/metabolismo , Proteínas Musculares/metabolismo , Atrofia Muscular/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/patologia , Animais , Músculos Laríngeos/patologia , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Knockout , Proteínas Musculares/genética , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/genética , Atrofia Muscular/patologia , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases/genética , Prega Vocal/metabolismo , Prega Vocal/patologia , Síndrome de Emaciação/induzido quimicamente , Síndrome de Emaciação/genética , Síndrome de Emaciação/metabolismo , Síndrome de Emaciação/patologia
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